HIV-associated neurocognitive disorders (HAND) continue to be a remarkably prevalent condition in HIV- infected individuals despite the potent effects of combination antiretroviral therapy (cART). The development of HAND represents an important treatment issue for HIV patients that impacts quality of life, mortality, and everyday functioning. Currently, despite 25 years of research, no specific treatments have entered clinical practice for HAND. The overarching aim of this proposal is the development of a novel therapy, intranasal insulin, for HIV-associated neurocognitive disorders (HAND). We have identified this as an innovative, and high potential target based on our preliminary research. HIV-infection and cART are well known to cause alterations in lipid distribution, glucose homeostasis, and energy metabolism that are associated with alterations in insulin signaling. Several decades of research have shown that insulin has multiple actions in brain that regulate many of the same neural pathways perturbed by HIV infection including energy metabolism, lipid metabolism, neurotransmitter channel activity, neurite outgrowth, synaptic strength, and inflammatory signaling suggesting that insulin might protect the CNS in the setting of HIV-infection. In preliminary experiments we found that insulin protected neurons from a broad variety of insults including toxic HIV proteins, as well as ischemic, oxidative, inflammatory, and excitotoxic challenges, in addition to dampening the inflammatory response of microglia. In a novel animal model of HAND produced by infection of conventional mice with a chimeric HIV (EcoHIV) we found that intranasal insulin treatment for 9 days completely reversed cognitive impairment in infected animals. These data are consistent with human studies in healthy volunteers, Alzheimer's and type 2 diabetes patients showing that intranasal insulin improves cognitive function. These preliminary findings strongly suggest that insulin delivered directly to brain may preserve or restore neuronal function in HIV-infected individuals.